The stability of thiamine in total parenteral nutrition mixtures stored in EVA and multi-layered bags

The compounding of complete total parenteral nutrition (TPN) mixtures into big bags with extended shelf-lives has been made more possible by the introduction of reduced gas permeable bags, using multi-layered plastic laminates. Since this produces a highly reduced chemical environment, the stability of thiamine; which degrades by reduction, may be compromised. It was the purpose of this study to investigate the degradation of thiamine at two different concentrations in TPN mixtures containing different commercial amino acid sources stored for extended periods in EVA or multi-layered bags. Results indicated that thiamine was unstable in mixtures containing Freamine III 8.5%, a metabisulphite-containing amino acid infusion, but was relatively stable in mixtures containing Vamin 14, Aminoplex 12 or Eloamin 15% as the amino acid source. Degradation of thiamine in Freamine III 8.5%-containing mixtures stored in multi-layered bags was more rapid than in EVA bags. Degradation rate was not greatly influenced by thiamine concentration. Results indicate that thiamine is stable in complete TPN mixtures for periods of at least 28 days in multi-layered bags, provided metabisulphite containing amino acid infusions are avoided. The shelf-life of complete mixtures containing Freamine III should be restricted to ensure patient receive minimum acceptable daily thiamine requirements.     

In vitro and clinical studies on intravenous feeding mixtures comprising fat emulsion, amino acid and electrolytes

This paper describes the effect of the amino acid mixture Freamine II on the physical stability of Intralipid fat emulsion. The amino acid-fat emulsion mixture was also administered to patients requiring intravenous nutrition and its clinical and biochemical effects were assessed. The amino acid-fat emulsion mixture was stable on storage for 48 hours as judged by flocculation and particle growth measurements made in the presence of 20 mmol/1 monovalent cations at 2 mmol/1 diavalent cations. Long-term storage of mixtures containing Freamine II is not recommended because of an interaction between the emulsifier and the amino acids. In a small open trial patients maintained their serum albumin concentrations. There was no evidence of impaired pulmonary function even in those subjects with impaired fat clearance.     

Precipitation of trace elements in parenteral nutrition mixtures

Trace elements are an essential additive to parenteral nutrition (PN) mixtures. Previous studies have indicated that certain trace elements, in particular copper and iron, may interact with complete PN mixtures leading to precipitate formation. The causes of these incompatibilities have not been fully elucidated. The purpose of this study was to determine factors responsible for common trace element incompatibilities, using X-ray energy dispersive spectroscopy to examine the elemental content of precipitates isolated from stored PN mixtures with added trace elements. Results indicated that copper sulphide precipitated most rapidly in PN mixtures containing Vamin 9 and in mixtures stored in multilayered bags. Copper sulphide precipitation was delayed in PN mixtures containing Vamin 14 and was not observed in PN mixtures stored in EVA bags. Iron phosphate precipitates were observed in Synthamin-containing PN mixtures after storage, but this was prevented in mixtures containing vitamins stored in multilayered bags.     

Availability of insulin from total parenteral nutrition solutions

Insulin is frequently required in total parenteral nutrition (TPN) solutions to control hyperglycemia. The purpose of this study was to evaluate the recovery of human insulin from standard TPN solutions with and without lipids and from TPN solutions with specialized amino acid formulations and to compare it to the insulin recovery from normal saline. All solutions were mixed in currently utilized PVC-free bags (ethylene vinyl acetate) and drained through PVC-containing tubing. Human insulin (Humulin-R) was spiked with 125I-labeled insulin and then added in concentrations of 10, 25, and 50 units to 1-liter bags containing 39-g amino acids (10% Freamine-III; or 6.9% Freamine HBC; or 8% Hepatamine), 257-g dextrose, electrolytes (Hyperlyte-R), 1000 units of heparin, MVI-12, and MTE-5 Concentrate. Alternate sets of bags contained 125 ml of 20% Intralipid and an appropriate amount of sterile water to keep the final volume at 1 liter. Actual clinical conditions of preparation, storage, and administration were simulated in this in vitro experiment. Multiple samples were collected during the 8-hr infusion period directly in gamma counter vials. All experiments and assays were done in triplicate. Our findings indicate that human insulin availability in TPN solutions is much higher (90%-95%) than the 50% suggested in the literature. Insulin recovery was not appreciably altered by adding lipids or by using Freamine HBC. Insulin recovery from TPN solutions was significantly reduced if they contained Hepatamine (87% and 88%, p less than 0.05) as compared to Freamine (90% and 94%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Factors influencing the stability of ranitidine in TPN mixtures

The stability of ranitidine in TPN mixtures has been widely studied with varying results. The evidence suggests that ranitidine is unstable and should be added within 24 h of administration, although other reports indicate ranitidine is stable for at least 14 days. The causes of ranitidine degradation in TPN mixtures were therefore studied in mixtures without fat emulsion using a stability-indicating HPLC method. The results indicated that the stability of ranitidine at 5 degrees C depended on the commercial source of amino acid, additives and type of bag used. The principle mechanism of degradation was identified as oxidation. Ranitidine was more stable in EVA bags in the absence of the trace element additive, which appeared to accelerate ranitidine oxidation. Ranitidine was most stable in mixtures compounded in multi-layered bags. The results suggest TPN mixtures with ranitidine in multi-layered bags could be assigned shelf lives of at least 14 days at 5 degrees C, depending on the amino acid infusion used in the regimen.     

The effect of different intravenous nutritional regimens on renal function during acute renal failure in the rat

Acute renal failure in the surgical patient is accompanied by a state of hypermetabolism and increased catabolism. Nutritional therapy is therefore directed at the preservation of body cell mass and protein synthesis for repair of wounds and damaged renal tubuli and for maintenance of host defense mechanisms. We examined the effect of two levels of protein intake (18.4 +/- 1.4 and 30.8 +/- 2.4 mg N/100 g BW/day) and three different amino acid formulations (Freamine III, Nephramine, and a made-up mixture of Nephramine + Freamine HBC) on renal function following mercury chloride-induced acute renal failure in the rat. All animals suffered severe renal failure manifested by increased plasma urea and creatinine levels, decreased creatinine clearance, and increased fractional excretion of sodium. On day 4 of acute renal failure, rats receiving low dose amino acids had better-preserved renal function than those receiving high dose amino acids. However, the type of solution infused did not affect recovery of renal function.     

Effect of dietary mineral composition on nutritional equivalency of amino acid mixtures and casein in rats

The effect of dietary mineral composition on the quality of amino acid mixtures and intact casein was examined in growing rats fed for 28 days under "conventional" conditions. When 25% demineralized casein (DC) was the sole dietary protein source, the widely-used mineral mixture by Harper (MMH) supported growth poorly (3.2 g/day), but a new formula mineral mixture (MM2) containing sufficient amounts of zinc gave a growth rate of over 8 g/day for 21 days. With a crude casein (CC) diet, rats grew at the same rate regardless of mineral mixtures. The growth-supporting power of amino acid mixtures, one of which simulated casein (AA-A) and another patterned after Rogers and Harper to give maximal growth of rats (AA-B), was compared with those of DC and CC with addition of MMH or MM2. When the protein source was DC, AA-A or AA-B, MM2 significantly improved the growth over that of rats fed MMH. The growth-stimulating effect of MM2 was greater when added to DC diet than when added to AA-A diet. When MM2 was added to AA-B diet, the growth rate greatly increased and reached that of rats fed DC diet containing MM2 (over 8 g/day), showing a nutritional equivalency between the amino acid mixture and intact protein. Drawbacks inherent in MMH did not appear with CC diet, because CC contained considerable amounts of zinc. When a highly purified amino acid-sucrose diet is used, dietary minerals become most limiting for growth even under conventional conditions. Thus, the previous conflicting results concerning nutritional equivalency of amino acid mixtures and protein can be explained by inadequate mineral sources.     

Effect of parenteral glutamine supplementation on plasma amino acid concentrations in extremely low-birth-weight infants

BACKGROUND: Glutamine is one of the most abundant amino acids in both plasma and human milk and may be conditionally essential in premature infants. However, glutamine is not provided by standard intravenous amino acid solutions. OBJECTIVE: We assessed the effect of parenteral glutamine supplementation on plasma amino acid concentrations in extremely low-birth-weight infants receiving parenteral nutrition (PN). DESIGN: A total of 141 infants with birth weights of 401-1000 g were randomly assigned to receive a standard intravenous amino acid solution that did not contain glutamine or an isonitrogenous amino acid solution with 20% of the total amino acids as glutamine. Blood samples were obtained just before initiation of study PN and again after the infants had received study PN (mean intake: 2.3 +/- 1.0 g amino acids x kg(-1) x d(-1)) for approximately 10 d. RESULTS: Infants randomly assigned to receive glutamine had mean plasma glutamine concentrations that increased significantly and were approximately 30% higher than those in the control group in response to PN (425 +/- 182 and 332 +/- 148 micromol/L for the glutamine and control groups, respectively). There was no significant difference between the 2 groups in the relative change in plasma glutamate concentration between the baseline and PN samples. In both groups, there were significant decreases in plasma phenylalanine and tyrosine between the baseline and PN samples; the decrease in tyrosine was greater in the group that received glutamine. CONCLUSIONS: In extremely low-birth-weight infants, parenteral glutamine supplementation can increase plasma glutamine concentrations without apparent biochemical risk. Currently available amino acid solutions are likely to be suboptimal in their supply of phenylalanine, tyrosine, or both for these infants.     

Parenteral nutrition-induced hypersensitivity in an adolescent

A case report of a 15-year-old adolescent male who developed a hypersensitivity reaction to a parenteral nutrition (PN) solution containing multivitamins (MVI) is presented. Within 30 minutes after initiation of PN and lipids, the patient developed a total-body pruritic urticarial rash that resolved after discontinuation of the infusions and administration of diphenhydramine. Rechallenge with the same PN solution excluding heparin, as well as lipids, resulted in a similar urticarial reaction that also resolved within 30 minutes after discontinuation of the infusions and administration of diphenhydramine. Another rechallenge with a solution containing dextrose and amino acids at the same concentrations contained in the original PN solution did not elicit an allergic reaction, whereas addition of MVI to the dextrose and amino acids resulted in a similar allergic reaction 20 minutes after the start of the infusion. It was determined that the MVI component of the PN was the most likely causative agent of this patient's urticarial reaction.     

Degradation and outflow of amino acids from the rumen of sheep

1. In hay-fed, cannulated sheep the apparent degradation in and outflow from the rumen were determined for graded doses of mixtures of the amino acids lysine, threonine and methionine, administered intraruminally and using polyethylene glycol (PEG) as a liquid marker. The doses ranged between 2.5 and 15 g for each amino acid in the mixtures. 2. Relative rate of apparent degradation in the first 4 h was highest for lysine, and lowest for methionine. The apparent degradation in 24 h was highest for lysine and lowest for threonine. Conversely the fraction flowing out of the rumen in intact form in 24 h was highest for threonine and lowest for lysine. Rates of apparent degradation as well as outflow were dose-dependent. 3. The validity of the estimated outflow of amino acids from the rumen was corroborated by measurements of concentrations of the amino acids in duodenal contents and in blood plasma which were also dose-dependent. 4. It was concluded that part of the requirement for the essential amino acids threonine and methionine may be met, even when these amino acids are delivered in unprotected form, given as a feed supplement.     

Oligopeptide mixtures produced from soy protein by enzymatic modification and their nutritional qualities evaluated by feeding tests with normal and malnourished rats

Soy protein isolate (SPI) was enzymatically modified to produce oligopeptide mixtures having methionine at approximate levels of 1% and 3%. Each of them had an average molecular weight of slightly lower than 1,000 daltons. They were compared with corresponding amino acid mixtures as well as with SPI for protein efficiency ratio (PER) and several other parameters. Normal and protein-malnourished rats were used as subjects for the comparison tests. When malnourished rats were subjected to a feeding test at a methionine level of 1% in nitrogen source, the oligopeptide mixture, OPM1, gave a significantly higher PER value than any of SPI and the amino acid mixtures. At a methionine level of 3%, both normal and malnourished rats utilized the oligopeptide mixture, OPM3, with higher efficiency than the amino acid mixture. These results suggest that the oligopeptide mixtures were utilized similarly to or more efficiently than SPI from which they were derived and the amino acid mixtures with exactly simulated amino acid composition.     

Comparison of the Rates of Vitamin Degradation when Mixed with Metal Sulphates or Metal Amino Acid Chelates

Mixes containing retinol, cholecalciferol, tocopherol, menadione, thiamin, riboflavin, pyridoxine, cyanocobalamin, ascorbic acid, nicotinamide, pantothenic acid, folic acid, and biotin were blended with either metal sulphates or metal amino acid chelates of Cu, Zn, Fe, Mn, and Co. Half of the mixes were stored at 37°C and the other half at 20°C. Vitamin potencies were determined at 0, 90, and 180 days. The percentages of losses of retinol, menadione, pyridoxine, and ascorbic acid were significantly less when these vitamins were stored with metal amino acid chelates compared to storage with metal sulphates at either temperature. There was significant degradation of pyridoxine and riboflavin at 37°C and of ascorbic acid, retinol, and menadione at 20°C in the presence of the metal sulphates, but not in the presence of the amino acid chelates. It was concluded that in stored foods containing vitamins and minerals, there would be significantly less degradation of the vitamins prone to oxidation if the sources of the added minerals were amino acid chelates.     

Bioavailability of pyridoxine-5'-beta-D-glucoside determined in humans by stable-isotopic methods

Stable-isotopic methods were employed to evaluate the utilization of dietary pyridoxine-5'-beta-D-glucoside (PN-glucoside), a major form of vitamin B-6 in plant-derived foods, as a source of available vitamin B-6 for adult men (20-35 y old, n = 5). Deuterium-labeled forms of free pyridoxine (PN) and PN-glucoside were compared using the urinary excretion of labeled forms of the vitamin B-6 metabolite 4-pyridoxic acid as the main index of absorption and metabolism. When comparing orally administered, isotopically labeled PN and PN-glucoside in separate groups of subjects, similar bioavailability was observed although within-group variability was high. A dual-label study designed to examine the bioavailability of these compounds when administered simultaneously indicated that the utilization of deuterated PN-glucoside was 58 +/- 13% (mean +/- SEM) relative to that of deuterated PN. PN-glucoside was detected in all urine samples, which provided additional evidence of incomplete metabolic utilization. In contrast, intravenously administered PN-glucoside underwent approximately half the metabolic utilization of oral PN-glucoside. These studies indicate that the bioavailability of dietary PN-glucoside, although incomplete, is substantially greater in humans than previously found in rats. In addition, the difference between oral and intravenous routes suggests a role of beta-glucosidase(s) of the intestinal mucosa, microflora, or both in the release of free PN from dietary PN-glucoside.     

Calcium chloride and sodium phosphate in neonatal parenteral nutrition containing TrophAmine: precipitation studies and aluminum content

Objectives: The objectives were to determine concentrations of calcium chloride (CaCl) and sodium phosphate (NaPhos) that can be safely added to TrophAmine‐based parenteral nutrition (PN) and to measure aluminum (Al) concentrations in PN solutions containing CaCl and NaPhos vs those containing calcium gluconate (CaGlu) and potassium phosphate (KPhos). Methods: In study A, PN solutions containing varying amounts of TrophAmine, CaCl, and NaPhos were compounded and then evaluated visually for precipitation. In study B, Al concentrations were measured in PN solutions containing CaCl and NaPhos (S1), CaGlu and NaPhos (S2), or CaGlu and KPhos (S3). Results: Study A showed that a maximum phosphorus concentration of 15 mmol/L could be added to a solution containing 12.5 mmol/L of calcium without evidence of precipitation when the amino acid (AA) concentration reached ≥3 g/dL (3%). In study B, the mean (range) Al concentrations were S1 = 2.2 (1.9–2.4), S2 = 8.5 (7.8–9.3), and S3 = 11.7 (10.8–12.2) µmol/L (means of 6.0, 22.9, and 31.5 micrograms/dL, respectively). Conclusions: The data can provide a guide for compounding neonatal PN solutions containing TrophAmine, CaCl, and NaPhos. More studies are needed to determine the long‐term effects of substituting CaCl for CaGlu in PN solutions for neonates. Substituting CaCl and NaPhos for CaGlu and KPhos significantly decreases Al concentrations in PN and potential Al exposure of neonatal patients.     

Low Availability of Aluminum in Formulations for Parenteral Nutrition Containing Silicate

Background: Silicate (Si) and aluminum (Al) may be concomitant impurities in solutions for parenteral nutrition (PN). Silicate can bind to Al to form stable hydroxyaluminosilicates (HAS), thus reducing Al availability. This possibility is investigated by heating solutions containing constituents of PN in glass containers to promote the release of Si and Al. Methods: The total amount of Si and Al in solution is measured by atomic absorption spectrometry, and the Al not bound to Si is evaluated by reaction with morin. Results: When the Si:Al molar ratio is >5, no free Al is found in solution. For ratios <5, it is found that the lower the ratio, the higher the free Al fraction. However, in solutions of some amino acids, even with a low Si:Al ratio (<2), the amount of free Al is lower than that found in other solutions. The same tendency is observed among commercial formulations. Although in salt solutions the free fraction of Al reaches almost 100% when the Si concentration is low, in amino acid formulations the free fraction of Al does not surpass 50%. Moreover, even for Si:Al ratios >5, there is a “residual” fraction of free Al in amino acid formulations. Conclusions: The concomitant presence of Al and Si in solutions for PN reduces the amount of Al available attributable to the formation of HAS. In amino acid formulations this effect may be slightly reduced given the affinity of certain amino acids for Al. Therefore, amino acids may behave in the same fashion as silicate.     

Micronutrient supplementation in parenteral nutrition in Spanish hospitals

Several years ago, it was recommended not to add vitamins or oligoelements to parenteral nutrition (PN) solutions and to administer them immediately after the addition of the micronutrients to avoid their decay. Nowadays, it has been observed that with multilayer bags, ternary mixtures and sunlight protection vitamins degradation is minimal. Daily intake of micronutrients is necessary in the critically ill, malnourished or long-term PN patients. Aiming at knowing the schedules of use of micronutrients in PN in Spanish hospitals and the way PN bags are prepared regarding the factors conditioning their stability, we undertook a telephone survey to the pharmacists in charge of PN at the different hospitals. We compared the data obtained with those from other surveys performed in 2001 and 2003. Pharmacists from 97 hospitals answered the questionnaire (answer rate 88%). The hospital sizes ranged 104-1728 beds. As compared to the data form preceding years, we observed a better adequacy to the current recommendations, although there are still 30% of the hospitals that administer micronutrients on an every other day basis independent of the clinical situation of the patients. In most of the hospitals, multilayer bags are used and/or sunlight protection and ternary mixtures. According to these results showing the different criteria for administering vitamins and oligoelements in PN solutions, it seems necessary to elaborate consensus documents that adapt to the reality of the diverse practices besides promoting the performance of well-designed clinical studies establishing the requirements under special clinical situations.     

The stability of ascorbic acid in TPN mixtures stored in a multilayered bag

Because of the susceptibility of some vitamins to oxidation, they are not normally added to TPN mixtures until shortly before addministration. Vitamin C (ascorbic acid) is oxidised rapidly, especially in the presence of trace elements. The aim of this study was to investigate the stability of ascorbic acid in complete TPN mixtures in Ultrastab multilayer bags, which are designed to reduce oxygen transmission and thus oxidation, in comparison with standard EVA bags. Ascorbic acid content was determined in two typical TPN mixtures providing 16 g nitrogen, 2000 kilocalories, electrolytes, trace elements and multivitamins, with and without fat emulsion, during storage at 5 degrees C for up to 3 months. In EVA bags ascorbic acid degraded by more than 75% during 24 h and was undetectable in 2-3 days. In contrast, there was a comparatively small initial loss of 15-30% ascorbic acid in mixtures stored in multilayer bags, with little further loss during 1-3 months. Bags containing fat emulsion retained higher concentrations of ascorbic acid after storage compared to those without fat emulsion, but all mixtures in multilayer bags maintained 60-80% ascorbic acid activity after 3 months. Since ascorbic acid is the most oxygen-sensitive vitamin, complete TPN mixtures with vitamins could be compounded in multilayer bags for an extended shelf life, rather than admixing just prior to administration.     

The photodegradation of vitamins A and E in parenteral nutrition mixtures during infusion

BACKGROUND & AIMS: Vitamins A and E are the most light-sensitive vitamins. Vitamin A is degraded by photolysis, while vitamin E degrades by photo-oxidation. The composition of the parenteral nutrition mixture and the container could therefore influence degradation during daylight administration. The aim of this study was therefore to determine the influence of fat emulsion and the type of bag on the photo-degradation of vitamins A and E in Parenteral Nutrition (PN) mixtures during simulated infusion in daylight. METHODS: Representative adult PN mixtures, with and without fat emulsion, were prepared. Samples for analysis were taken from infusates and each bag during simulated infusion. Degradation of vitamins A and E was determined by stability-indicating HPLC analysis. RESULTS: Results indicated that vitamin A loss proceeded rapidly during infusion, resulting in up to 80% loss in 6 hours, even with light protection of the bag. The presence of fat emulsion did not provide significant light protection. Vitamin E degradation was substantial if mixtures were prepared in EVA bags but was largely prevented if PN mixtures were compounded and stored in multi-layered bags. CONCLUSIONS: It is recommended that all PN bags should be light-protected during infusion in daylight. The use of multi-layered bags will prevent vitamin E losses during infusion.     

Infusion of a branched-chain amino acid-enriched solution and alpha-ketoisocaproic acid in septic rats: effects on nitrogen balance and skeletal muscle protein turnover

Sepsis was induced by cecal ligation and puncture in male Sprague-Dawley rats weighing approximately 70 g and the animals were intravenously infused with one of four isocaloric solutions: group I (N = 16), 8.5% dextrose solution; group II (N = 16), alpha-ketoisocaproic acid (KIA, 5.1 mg/ml) in 8.5% dextrose; group III (N = 16), FreAmine HBC (containing 45% branched-chain amino acids) in 2.5% dextrose; and group IV (N = 17), FreAmine HBC in 2.5% dextrose + KIA (5.1 mg/ml). Eighteen hr after induction of sepsis, extensor digitorum longus (EDL) and soleus (SOL) muscles were dissected with intact tendons and incubated for the study of protein synthesis and degradation, which were measured as incorporation of 14C-phenylalanine into protein and release of tyrosine into incubation medium, respectively. Urine was collected for determination of nitrogen balance. Nitrogen balance, which was equally negative in groups I and II, was significantly improved in groups III and IV and became equally positive in these groups. Protein synthesis and degradation rates in incubated EDL and SOL muscles were similar to those which we have reported previously in septic rats. Except for a higher synthetic rate in SOL in group II, no other differences in protein synthesis or degradation rates between the four experimental groups were found. Thus, the present study showed that infusion of a branched-chain amino acid-enriched solution improved nitrogen balance in septic rats. KIA alone or administered with the amino acid solution did not affect nitrogen balance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Case report of an allergic reaction to parenteral nutrition in a pediatric patient

We report a 34-month-old girl with stage IV neuroblastoma who developed hives when parenteral nutrition (PN) containing amino acids, dextrose, electrolytes, minerals, vitamins, and trace elements was infused. Administration of diphenhydramine resulted in disappearance of the rash. Infusion of the PN solution without intravenous fat emulsion produced a similar rash with itching. The pediatric multiple vitamin (PMV) preparation was removed from the PN formula and the formula was infused without incident. The patient was maintained on PN and an oral vitamin supplement with no further complaints. Inadvertent administration of a PN solution containing PMV resulted in a recurrence of hives. Absence of any adverse reactions when the PMV preparation was removed from the PN solution and an allergic reaction when the multivitamin was added to the PN solution support the possibility that the allergic reaction was related to the infusion of the multiple vitamin preparation.